The aim of this study was to examine the effect of genistein on human neuroblastoma cell proliferation induced by two common environmental endocrine disruptors, bisphenol A (BPA) and Di-2-ethylhexyl phthalate (DEHP), and to investigate its underlying mechanism. SK-N-SH human neuroblastoma cells were treated with E2 (1 ng/ml), BPA (2 μg/ml) or DEHP (100 μM), with or without genistein (12.5 μM) in vitro. The number of viable cells was detected with an absorbance reader after 0, 24, 48 or 72 h treatment. The percentage of cells in different phases, and expression of Akt and its phosphorylation levels were also assessed by flow cytometry and western blot analysis at 72 h, respectively. The BPA and DEHP groups had a 30% higher number of viable cells compared to the non-treated group at 48 h (P<0.001). However, the cell numbers did not increase significantly in the groups with additional treatment with genistein (P>0.05 vs. control) and the same trend was observed at 72 h. The expression of phospho-Akt protein was increased in the groups treated with BPA or DEHP compared to the control group at 72 h (P<0.05), while no significant elevation in the expression of phospho-Akt was observed (P>0.05) in genistein-treated groups. Cells were arrested at the G2/M phase by genistein. Similar effects were observed in the E2 group with or without genistein treatment. Akt protein expression had no significant change among all the groups (P>0.05). In conclusion, estradiol- or environmental endocrine disruptor-induced proliferation of human neuroblastoma cells is effectively abolished by genistein, likely in a cell cycle- and Akt pathway-dependent manner.